What is the initial investigation for a 3-month-old baby with microcephaly and normal development?

Investigation of a 3-Month-Old Baby with Microcephaly and Normal Development

For a 3-month-old infant with microcephaly but otherwise normal development, begin with brain MRI to identify structural abnormalities, followed by detailed perinatal history-taking to assess for congenital infections and teratogen exposures, and proceed with chromosomal microarray analysis (CMA) as first-tier genetic testing. 1

Initial Clinical Assessment

Essential History Components

• Perinatal history: Specifically inquire about maternal fever, rash, or flu-like illness during pregnancy; alcohol or drug exposure; and birth complications including placental insufficiency 1
• Family history: Document any relatives with developmental delays, microcephaly, recurrent pregnancy loss, stillbirth, or infant death to identify potential genetic etiologies 1
• Growth trajectory: Review serial head circumference measurements from birth, as deceleration of growth rate is more significant than a single measurement 2
• Dysmorphic features: Examine for facial dysmorphisms, congenital abnormalities outside the CNS, and skin lesions that may indicate specific genetic syndromes 1

Physical Examination Priorities

• Ophthalmological examination: This should be performed routinely in every infant with microcephaly, as up to 48% have ocular abnormalities including chorioretinitis (CMV, toxoplasmosis), chorioretinopathy (KIF11 mutations), or retinal abnormalities (Zika virus) 1
• Neurological tone assessment: Evaluate for hypertonia (suggesting upper motor neuron pathology) versus hypotonia (suggesting neuromuscular or metabolic disorders) 1
• Organomegaly and cardiac examination: Hepatomegaly may suggest metabolic disorders like peroxisomal disease 1

Neuroimaging

Brain MRI is the first-line imaging modality and should be performed preferably before sedation is required (ideally before 5 months corrected age). 1, 3

What to Look For on MRI

• Signs of fetal injury: Gliosis, cysts, and calcifications suggest congenital infection or vascular injury 1
• Cortical malformations: Polymicrogyria, lissencephaly, or simplified gyral patterns may indicate genetic causes or fetal injury 1
• White matter abnormalities: Hyperintensities suggest congenital CMV infection (seen in 12-30% of polymicrogyria cases) 1
• Structural abnormalities: Corpus callosum hypoplasia, ventriculomegaly, or posterior fossa abnormalities 1

The diagnostic yield of neuroimaging ranges from 43-80%, with higher yields in severe microcephaly (head circumference <-3 SD) 3. Normal neuroimaging does not exclude the diagnosis but makes acquired causes less likely 1.

Infectious Disease Workup

If congenital infection is suspected based on history or imaging findings (calcifications, white matter changes, chorioretinitis), test for TORCH infections. 1

• CMV testing: Retrieve the Guthrie neonatal blood spot for CMV PCR if available, as CMV accounts for 12-30% of microcephaly cases with polymicrogyria 1
• Additional testing: Consider toxoplasmosis, syphilis, varicella zoster, and Zika virus serology based on maternal exposure history and clinical/imaging findings 1
• Clinical clues: Congenital sensorineural hearing loss, hepatosplenomegaly, or specific retinal findings increase suspicion 1

Genetic Testing Algorithm

First-Tier: Chromosomal Microarray Analysis (CMA)

CMA should be the initial genetic test, as it detects chromosomal aneuploidies (59% of genetic cases), copy number variations (18% of genetic cases), and submicroscopic deletions/duplications. 1, 4

• CMA is particularly important as non-genetic causes (infections, teratogens, perinatal injury) account for only 30% of microcephaly cases, meaning 70% have genetic etiologies 1
• Common findings include 22q11.2 deletion, 1p36 deletion, and other pathogenic CNVs 1

Second-Tier: Whole Exome or Genome Sequencing

If CMA is negative and clinical features suggest a genetic syndrome, proceed with trio-based whole exome sequencing (WES) or whole genome sequencing (WGS). 1

• Single gene disorders account for 23% of genetic microcephaly cases 4
• The diagnostic yield of standard genomic testing is approximately 20% 1
• Consider targeted gene panels if specific syndromes are suspected (e.g., WDR62 for microcephaly with polymicrogyria) 1

Karyotype Analysis

Consider karyotype if CMA and sequencing are unrevealing, as balanced translocations and ring chromosome abnormalities are rare but recognized causes. 1

Metabolic Testing (Selective)

Metabolic screening is NOT routine but should be pursued if specific clinical features are present. 1

• Peroxisomal disorders: Test plasma very long chain fatty acids (VLCFAs) if the infant appears unusually sick for a static brain malformation, has profound hypotonia, hepatomegaly, dysmorphic features, or severe leukoencephalopathy on MRI 1
• Thyroid function: Consider TSH and T4 if there are signs of hypothyroidism, though newborn screening typically identifies congenital cases 1
• The prevalence of metabolic disorders in microcephaly is estimated at only 1% 3

Screening for Associated Conditions

Even with normal development at 3 months, screen for coexistent conditions that may emerge later. 3

• Epilepsy: Present in approximately 40% of children with microcephaly 3
• Cerebral palsy: Occurs in approximately 20% 3
• Developmental delay: Affects approximately 50%, though more common in severe microcephaly (<-3 SD) 3
• Ophthalmologic disorders: Present in 20-50% 3

Critical Pitfalls to Avoid

• Do not assume normal development at 3 months excludes significant pathology: Children with mild microcephaly (-2 to -3 SD) have approximately 40% risk of imaging abnormalities and developmental impairments, while severe microcephaly (<-3 SD) carries 80% risk 3
• Do not rely on negative maternal history to exclude infections: A negative history cannot reliably rule out teratogen exposure or congenital infections 1
• Do not overlook craniosynostosis: This represents microcephaly without true micrencephaly due to premature suture fusion and requires different management 5, 6
• Serial measurements are essential: A single normal measurement does not exclude evolving microcephaly; deceleration of head growth velocity may be the only early clue 2

Prognostic Considerations

The prognosis depends heavily on the underlying etiology rather than head circumference alone 7. Outcomes are generally worse for:

• Intrauterine infections 7
• Chromosomal abnormalities 7
• Metabolic disorders 7
• Severe microcephaly (<-3 SD) with associated brain malformations 3